Toxins in the body (human or animal) may be of either external origin or a result of physiologic processes. Where renal or hepatic failure or insufficiency hampers normal metabolism or excretion of waste products or toxins, serious illness or death results, even though the waste products or toxins may be normally present in the body in non-toxic concentrations.
Although antidotes sometimes may be employed for specific toxins, at the present time, treatments for toxins in the body typically involve either replacement of body fluids (e.g., blood or plasma replacement/transfusion) or purification of the blood by external means. An example of such blood purification is the fairly common process of renal dialysis (either standard or peritoneal). In the most common methods of dialysis, highly pure water on one side of a membrane (e.g., the peritoneum or an artificial membrane in a dialyzer) is used to create osmotic transport of toxins from the blood to the water. The water, after passing once through the dialyzer, is discharged to the drain. In a standard dialysis system, the patient's blood is pumped through the dialyzer, while the highly pure water, combined with essential electrolytes, is passed through the dialyzer on the opposite side of the dialyzer membrane.
Where a large supply of highly pure water is not available or undesirable, it is possible to re-circulate the dialysis water by purifying it. Such purification is accomplished with active carbon, often in conjunction with ion-exchange media. The Redy™ 2000 and Allient™ dialysis machines are examples of such a system. In these machines, the dialysate is purified (regenerated) by layers of granular carbon and ion exchange resins in a single cartridge (the Sorb™ column). In principle, multiple cartridges, each containing a single substance, could be connected in series to achieve the same result. The active carbon adsorbs various toxins. Hemodialysis circuits are typically clean, but not sterile. The Sorb column is also clean, but not sterile and the carbon layer actually removed many bacteria. Since the dialysis treatments of the Redy and Allient machines were of limited duration, up to 8 hours, recirculating dialysate through the Sorb column did not result in significant growth of bacteria in the dialysate.
Another method of blood purification is hemoperfusion, where the patient's blood is pumped directly through a bed of granular active carbon. The active carbon adsorbs toxins directly from the blood. This method is rarely used due to thrombogenicity and other issues.
In other, typically more recent and experimental extracorporeal treatments, plasma is separated from the patient's blood by a filter or centrifuge. The plasma is then treated by contact with purification media such as active carbon and/or ion exchange media, which adsorb toxins from the plasma.
Of interest here is the role of active carbon. Carbon is a natural adsorbent for many organic compounds including toxins. Thermal, steam, or chemical treatment of carbon can create a highly porous form of carbon with very high surface area per unit weight, typically on the order of 100 to 2000 square meters per gram. Such treated carbon is called, variously, activated carbon, activated charcoal, active carbon, active charcoal, etc. The term “active carbon” is used herein. The pore structure of active carbon is commonly classified according to size as macropores, mesopores and micropores. See FIG. 1. It is the pore structure which gives active carbon its high surface area per unit weight, and thus its “activity” or affinity which enables it to adsorb significant and useful quantities of toxins. Toxins thus adsorbed are thus, obviously, removed from the patient.
Pores typically become finer as one penetrates deeper into a particle of carbon. The larger, outer, macropores lead to the smaller mesopores (variously defined as being 2-100 μm), which in turn, lead to the yet smaller micropores (variously defined as <2-10 μm).
Since adsorption is a physical, equilibrium-governed process, particles of carbon will rapidly and immediately adsorb a small initial charge of toxin, but then adsorption will cease unless the toxin diffuses into the pore structure of the carbon particle where the toxin is able to reach areas of low toxin concentration. Hence, diffusion of the toxin into the interior pore structure is critical as most of the available surface area of the carbon is in the pore structure, particularly the mesopores and micropores. This being the case, highly microporous carbons are typically selected for small molecular weight toxins and highly mesoporous carbons are typically selected for larger molecular weight toxins. Where mixes of toxins are encountered, a carbon with a mix of mesopores and micropores will be selected.
Many processes govern diffusion of molecules into the pores. In generalhowever, the longer the pore, the more time it will take for target molecules to reach the inner portions of the pores. The result is that the larger the particle of active carbon, the slower the diffusion of target (toxin) molecules into the pores and the slower the adsorption kinetics, other parameters being equal.
One obvious method of reducing the mean path length of the pore structure is to use smaller particles of carbon. Whereas industrial purification processes typically use granular carbon and treatment times of hours, carbon given as general oral antidote for poisoning is finely powdered.
FIG. 2 compares the effects of particle size on adsorption kinetics. In FIG. 2, reaction time was limited. During this time, the same granules which adsorbed little bilirubin (a typical toxin) adsorbed much more bilirubin when powdered. The very finely powdered oral adsorbent used as a general antidote to accidental poisoning (Norit Powder) adsorbed very much more bilirubin.
This phenomenon, at its core, is simple: Smaller particles have shorter mean pore length so they adsorb toxins more quickly.
When active carbon is used as an oral sorbent, or when employed in a suspension, very fine particles rapidly adsorb toxins and are thus much more effective than larger particles where time of contact between the active carbon and the solution containing the toxins is limited.
FIG. 3 is presented as an example of a use of fine particles of active carbon as an adsorbent to detoxify patient blood. The diagram shows an extracorporeal system using a suspension of finely pulverized (<10 μm, typical) active carbon. Blood is pumped from the patient through a filter, which may be a plasma filter, dialyzer or similar device. The filtrate (e.g., dialysate, albumin, or patient plasma) is passed through a reactor which mixes fine active carbon particles with the treated fluid, separates the treated fluid from the carbon, and returns the treated fluid either to the dialyzer or directly to the patient. This type of system is relatively fast and is therapeutically effective, but is costly and complex due to the need to separate very fine carbon particles from the exiting fluid.
It is important to note that in most cases, fluid volume is a critical limitation. There are two such limitations. First, to provide adequate treatment, i.e., to remove a clinically significant amount of toxin from the patient, a large volume of the patient's blood must be treated in a reasonable amount of time. Since treated blood is returned to the patient immediately, toxin removal follows an exponential decay curve. Secondary processes include diffusion of toxins from the interstitial fluid to the blood and from cells to the interstitial fluid and blood. FIG. 4 shows theoretical toxin removal by a perfect adsorbent over time for various plasma flow rates for a particular system which used a plasmafilter and an active carbon sorbent to treat rat plasma in a manner similar to that of FIG. 3, but which used solid block carbon.
As may be seen, improvements in plasma flow rate (Q) produce improvements in toxin clearance. The reason for this is that over a given period of time, higher flow rates treat more of the patient's blood and thus remove more toxin.
While the first volume limitation mandates a high treated fluid volume, safety considerations dictate that only a limited amount of blood may be withdrawn from a patient at any one time. Extracorporeal systems necessarily withdraw blood from the patient and present not only a short-term loss to the patient, but also present a hazard of long-term blood loss in the event of machine failure or clotting in the system. Hence, there is a second fluid volume limitation in that only a minimal amount blood is available for treatment at any one time.
In a particular practical extracorporeal system treating plasma, for example, plasma is presented to the active carbon for only seven minutes. Rapid adsorption kinetics is thus a necessity. Even in the case of regenerating aqueous dialysate, there may be practical fluid volume limitations, particularly when it is necessary to retain patient nutrients and desirable blood components which would otherwise be lost in standard “down the drain” hemodialysis.
As noted above, small particles may be used in a stirred suspension, but the apparatus is complex and costly. Packed columns would, at first, appear to be a reasonable alternative. Unfortunately, small particles present substantial hydraulic resistance when packed into a column. Making a column shorter and of increased cross-sectional area produces benefits, but this method has severe limitations due to problems with channeling in the charcoal bed, lack of even flow distribution and mechanical constraints. The problem is greatly compounded when the active carbon must treat proteinaceous fluids such as albumin or plasma which are viscous. The matter is more severe yet when column outlet frits (filters) must pass very large molecular weight substances found in plasma such as albumin and globulins. Carbon particle fines in the outlet frit may reduce the effective frit pore size to such small dimensions as to produce molecular sieving, a phenomenon which the inventors have observed. In certain cases, using high pressure can overcome some of these limitations, but this is costly, particularly where biohazard considerations dictate disposable wetted pump components.
We are thus left with the quandary that small particles give therapeutically useful fast sorption kinetics, while large particles may be readily contained in inexpensive columns which treat fluid at reasonable pressures. It is the object of the present invention to resolve this conundrum.
In general principle, an approach to providing a short mean diffusion path length in the pore structure of the carbon, while using large, easily-constrained carbon pieces, is to use large carbon pieces which are “geometrically complex” and which have a fine structure. A sponge roughly illustrates the concept. The sponge is a large object, but it has relatively small features. If the geometrically complex carbon is porous and allows the treated fluid to pass through it, then the useful fast reaction kinetics of small particles is provided by the small features. The overall particle is large and easily constrained in a reactor.
It is important to clarify some terminology at this point. Active carbon has a large surface area which is created by the pore structure. But we may define, “gross surface area,” as that surface which is presented by the outer surface outside of the pore structure. For example, generally spherical carbon particles of any size would have gross surface area of 4πr2. Obviously, the distinction between “gross surface” and the beginnings of the pores is fuzzy, but this does not invalidate the usefulness of the concept.
We desire pieces of carbon which have high gross surface area and fine features which give a short mean pore path length.
One form of geometrically complex active carbon that has been developed is fractal spherical carbon developed by Vladimir Nikolaev as shown in FIG. 5 which is used for hemoperfusion.
This carbon has performed well in specific applications, but is costly, not readily available and the spheres must be confined in a column by a frits or other means. Since the particles are on the order of 100 μm, pressure drop through a column, while not excessive, is significant, especially for plasma treatments.